JPH04134033A - Lyophilized preparation of ethoposide-2-dimethylamino compound - Google Patents

Abstract

PURPOSE:To provide the subject lyophilized preparation having good redissolubility, not depositing crystals, having good storage stability and substantially not producing decomposed products, by adding a nonvolatile acid and/or a salt thereof. CONSTITUTION:A lyophilized preparation used for preparing injection solutions contains (A) 4'-demethylepipodophyllotoxy-9-(4,6-o-ethylidene-2-dimethylamino-2- deoxy-beta-D-glucopyranoside) hydrochloride (ethoposide-2-dimethylamino compound), (B) a non-volatile acid such as inorganic acid, 6C hydroxycarboxylic acid, 4C dicarboxylic acid (particulary desirably phosphoric acid) and/or salts thereof, preferably alkali metal salts, and further optionally (C) a saccharide such as 5-6C sugar alcohol or disaccharide as a stabilizer in an A:B:C ratio of 10-95:5-50:0-80, especially 30-50:20-30:0-50, each % by weight.

Description

[Detailed description of the invention]

[0001]

[Industrial application field]

The present invention discloses 4'-demethylepipodophyllotoxin-9-(4,6-0-ethylidene-2-dimethylamino-2-deoxy-β-D-glucopyranoside) hydrochloride (hereinafter referred to as etoposide), which has antitumor activity. -2-dimethylamino compound). [0002]

[Conventional technology]

Since etoposide-2-dimethylamino compound is unstable in an aqueous solution state and difficult to store for a long period of time, it is necessary to make it into a powder preparation such as a freeze-dried preparation. [0003]

[Problem to be solved by the invention]

A preparation in which etoposide-2-dimethylamino compound is simply dissolved in distilled water and then lyophilized has the drawback that when it is redissolved, the pH of the solution increases and crystals precipitate.[000
4]

[Means to solve the problem]

Therefore, the present inventors conducted various studies on formulations for improving re-dissolution properties, and found that lyophilized formulations of etoposide-2-dimethylamino derivatives containing non-volatile acids and/or salts of these acids have good re-dissolution properties. The present invention was completed based on the discovery that crystals do not precipitate, the storage stability is good, and almost no decomposition products are generated, and that the storage stability can be further increased by adding sugars. [0005] The present invention relates to a lyophilized preparation of etoposide-2-dimethylamino compound containing a nonvolatile acid and/or a salt of the acid. [0006] Etoposide-2-dimethylamino compound used in the present invention is usually used in the form of hydrochloride as shown in JP-A-61-227590. In addition, hydrochloride has three polymorphic forms: an anhydrous crystal (hereinafter referred to as α crystal) and two types of dihydrate crystals (hereinafter referred to as β crystal and γ crystal), but any crystal form is It can be used according to the invention. [0007] The nonvolatile acids and salts of the acids used in the present invention are acids that have a buffering effect and are liquid or solid at room temperature, and the etoposide-2-dimethylamino form is relatively stable and has good solubility. There is no particular limitation as long as it is a physiologically acceptable acid or a salt of the acid that has the necessary buffering effect in the pH range of 3 or more and less than 5 and is used for medical purposes. Examples of these acids include inorganic acids such as phosphoric acid and sulfuric acid, and citric acid.
Oxycarboxylic acids with 6 carbon atoms (C6) such as gluconic acid, dicarboxylic acids with 4 carbon atoms (C4) such as succinic acid, tartaric acid, fumaric acid, maleic acid, carboxylic acids with 2 carbon atoms such as aminoacetic acid, etc. are mentioned, and phosphoric acid is more preferable. As salts of these acids, alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or magnesium salts can be used, but alkali metal salts are usually preferred. Two or more of these acids or salts thereof may be used in combination. The amount of these acids or salts thereof to be added to the preparation depends on the buffering effect of the acid or salt of these acids used, but approximately 1 part by weight of the non-volatile acid or salt thereof per 1 part by weight of etoposide-2-dimethylamino compound. 0.1 to about 5 parts by weight, preferably 1 to about 4 parts by weight, more preferably about 0.2 to about 3 parts by weight. Moreover, the pH of the formulation of the present invention is the pH of the redissolution solution.
H is about 3 or more and less than about 5, preferably about 3.0 or more and about 4.5 or less. [0008] If desired, saccharides and the like may be further added to the formulation of the present invention. Examples of sugars include mannitol, sorbitol,
Examples include sugar alcohols having 5 to 6 carbon atoms such as xylitol and inositol, and trisaccharides such as lactose, maltose, and sucrose. Among these, lactose is more preferred, although it is not particularly limited. By using these saccharides in combination, the storage stability of etoposide-2-dimethylamino compound is improved. The amount of these saccharides used is 0 to 30 parts by weight, preferably about 0.1 to 10 parts by weight, per 1 part by weight of etoposide-2-dimethylamino compound. From the viewpoint of formulation, it is preferably about 0.1 to 4 parts by weight. [0009] The proportion of each component in the lyophilized preparation of the present invention is about 10 to about 95% of the etoposide-2 dimethylamino form based on the entire preparation.
(w/w: hereinafter the same unless otherwise specified), preferably about 15 to about 80%, more preferably about 30 to about 50%,
Non-volatile acid or salt thereof about 5 to about 50%, preferably about 15 to about 35%: more preferably about 20 to about 30%,
Saccharides are preferably O to about 85%, preferably O to about 70%, and more preferably about 30 to about 50%. [0010] The lyophilized preparation of the present invention can be produced, for example, as follows. That is, etoposide-2-dimethylamino compound, a nonvolatile acid or its salt, and optionally a saccharide are dissolved in water for injection, and if necessary, the pH is adjusted to about 3 to about 5, preferably about 3.0 with sodium hydroxide or the like. An aqueous solution is obtained by adjusting the concentration to about 0 or more and about 4.5 or less. In addition, when using salts of these nonvolatile acids, etoposide-
In some cases, the 2-dimethylamino compound cannot be completely dissolved in water for injection. In this case, dissolution can be achieved by lowering the pH to slightly below 3 using a non-volatile acid. The preferred composition of this aqueous solution is about 5 to about 15 mg/ml of etoposide-2-dimethylamine, about 1 to about 10 mg/ml of a nonvolatile acid or its salt, and O to about 10 mg/ml of sugars.
Examples include those containing about 50 mg/ml. [0011] The freeze-dried preparation of the present invention is obtained by freezing the aqueous solution obtained as described above at -5 to -60°C, and then sublimating water under reduced pressure at a degree of vacuum of 001 to 200 Pa. The lyophilized preparation thus obtained is usually used by adding a dissolving solution such as water for injection to redissolve it and prepare it as an injection solution. Preferably, the pH of the solution is within the range of about 3 to about 5. [0012]

【Example】

Example 1 α crystals were dissolved in 50 mM phosphate buffer solution whose pH was adjusted to 3.0 by mixing 50 mM phosphoric acid water solution and 50 mM sodium dihydrogen phosphate solution so that the concentration was 10 mg/ml, and then dissolved in IN water. The pH was adjusted to 3.0 with sodium oxide solution. This solution was filled in 1 ml per vial and lyophilized to obtain product 1 of the present invention. (Approximately 63% etoposide-2-dimethylamino, phosphoric acid and its sodium salt approximately 37%)
[0013] Example 2 α crystals were 10 mg/ml and mannitol was 40 mg/ml.
ml in a 50 mM phosphate buffer solution with a pH of 3.0 in the same manner as in Example 1, and the pH was adjusted to 3.0 with IN sodium hydroxide solution. This solution was freeze-dried to obtain product 2 of the present invention. (Approximately 18% etoposide-2-dimethylamino, approximately 11% phosphoric acid and its sodium salt, and approximately 71% mannitol) [0014] Example 3 α crystals were 10 mg/ml, and inositol was 40 mg/ml.
ml in a 50 mM phosphate buffer solution with a pH of 3.0 in the same manner as in Example 1, and the pH was adjusted to 3.0 with IN sodium hydroxide solution. This solution was freeze-dried to obtain product 3 of the present invention. (Approximately 18% etoposide-2-dimethylamino, approximately 11% phosphoric acid and its sodium salt, and approximately 71% inositol) [0015] Example 4 Conducted so that α crystals were 10 mg/ml and lactose was 40 mg/ml. 50mM with pH 3.0 as in Example 1
Dissolve in phosphate buffer and p with IN sodium hydroxide solution.
H was adjusted to 3.0. This solution was freeze-dried to obtain product 4 of the present invention. (Approximately 1 etoposide-2-dimethylamino compound
8%, about 11% of phosphoric acid and its sodium salt, and 71% of lactose) [0016] Example 5 The pH was adjusted to 3.5% in the same manner as in Example 1 so that α crystals were 10mg/ml and maltose was 40mg/ml. 50m with zero
The solution was dissolved in M phosphate buffer and the pH was adjusted to 3.0 with IN sodium hydroxide solution. This solution was freeze-dried to obtain product 5 of the present invention. (Approximately 18% etoposide-2-dimethylamino, approximately 11% phosphoric acid and its sodium salt, and approximately 71% maltose) [0017] Example 6 Conducted so that α crystals were 10 mg/ml and white sugar was 40 mg/ml. 50mM with pH 3.0 as in Example 1
Dissolve in phosphate buffer and p with IN sodium hydroxide solution.
H was adjusted to 3.0. This solution was freeze-dried to obtain product 6 of the present invention. (Approximately 1 etoposide-2-dimethylamino compound
[0018] Example 7 A 50 mM citric acid aqueous solution and a 50 mM trisodium citrate aqueous solution were mixed so that the α crystals were 10 mg/ml, and the pH was adjusted. Dissolved in 50mM citrate buffer adjusted to pH 3.0, and adjusted to pH 3.0 with 50mM trisodium citrate aqueous solution.
Adjusted to. This solution was freeze-dried in the same manner as in Example 1 to obtain product 7 of the present invention. (approximately 49% etoposide-2-dimethylamino, citric acid and its sodium salt approximately 51%)
) [0019] Example 8 α crystals were 10 mg/ml, mannitol was 40 mg/ml.
ml in a 50 mM citrate buffer with a pH of 3.0 in the same manner as in Example 7, and the pH was adjusted to 3.0 with a 50 mM trisodium citrate aqueous solution. This solution was freeze-dried to obtain product 8 of the present invention. (Etoposide-2-
(about 17% dimethylamino compound, about 17% citric acid and its sodium salt, and about 66% mannitol) [0020] Example 9 β crystals were prepared as etoposide-2-dimethylamino hydrochloride to give a concentration of 10 mg/ml. It was dissolved in 50 mM phosphate buffer at pH 3.0 in the same manner as in Example 1, and the pH was adjusted to 3.0 with IN sodium hydroxide solution. 2 ml of this solution was filled per vial and lyophilized to obtain product 9 of the present invention. (Etoposide-2-dimethylamino form approx. 63
%, phosphoric acid and its sodium salt approximately 37%) [0021
] Example 10 Similarly to Example 9, β crystals were dissolved in the 50 mM phosphate buffer of Example 1 to a concentration of 10 mg/ml, and the pH was adjusted to 4.0 with IN sodium hydroxide solution. This solution was freeze-dried in the same manner as in Example 9 to obtain product 10 of the present invention. (
(approximately 63% etoposide-2-dimethylamino compound, approximately 37% phosphoric acid and its sodium salt) [0022] Example 11 β crystals were mixed in the same manner as in Example 9 at 10 mg/ml with a 25 mM phosphoric acid aqueous solution and 25 mM phosphoric acid. Dissolved in 25mM phosphate buffer, adjusted to pH 3.0 by mixing sodium dihydrogen aqueous solution, and adjusted to pH 3.0 with IN sodium hydroxide solution.
．． Adjusted to 5. This solution was freeze-dried in the same manner as in Example 9 to obtain product 11 of the present invention. (approximately 77% etoposide-2-dimethylamino, phosphoric acid and its sodium salt approximately 23%)
%) [0023] Example 12 β crystals were dissolved in a 50 mM aqueous phosphoric acid solution in the same manner as in Example 9 so that the concentration was 10 mg/ml and mannitol was 4 mg/ml, and the pH was adjusted to 3.
Adjusted to 5. This solution was freeze-dried in the same manner as in Example 9 to obtain product 12 of the present invention. (approximately 50% etoposide-2-dimethylamino, phosphoric acid and its sodium salt approximately 30%)
and Mannil I-le 20%) [0024] Example 13 β crystals were added at 10 mg/ml in the same manner as in Example 9, and lactose was added at 1
It was dissolved in a 50 mM aqueous phosphoric acid solution to a concentration of 0 mg/ml, and the pH was adjusted to 3.0 with an IN lithium hydroxide solution. This solution was freeze-dried in the same manner as in Example 9 to obtain product 13 of the present invention. (Approximately 37% etoposide-2-dimethylamino, approximately 26% phosphoric acid and its sodium salt, and 37% lactose) [0025] Example 14 β crystals were added at 10 mg/ml in the same manner as in Example 9, and sorbitol was added at 10 mg/ml. ml in 25mM phosphoric acid aqueous solution, and adjusted to pH 3.5 with IN sodium hydroxide solution.
Adjusted to. This solution was freeze-dried in the same manner as in Example 9 to obtain product 14 of the present invention. (Approximately 42% etoposide-2-dimethylamino, approximately 17% phosphoric acid and its sodium salt, and approximately 41% sorbitol) [0026] Example 15 β crystals were added at 10 mg/ml in the same manner as in Example 9, and xylitol was added at 10 mg/ml. ml in 25mM phosphoric acid aqueous solution, and adjusted to pH 3.5 with IN sodium hydroxide solution.
Adjusted to. This solution was freeze-dried in the same manner as in Example 9 to obtain product 15 of the present invention. (Approximately 42% etoposide-2-dimethylamino, approximately 17% phosphoric acid and its sodium salt, and approximately 41% xylitol) [0027] Control Example 1 α crystals were dissolved in water to a concentration of 10 mg/ml and diluted with IN hydrochloric acid. The pH was adjusted to 3.0 and freeze-dried in the same manner as in Example 1 to obtain Control Product 1. [0028] Control Example 2 A control product 2 was obtained by dissolving α crystals in water at a concentration of 10 mg/ml and lactose at a concentration of 10 mg/ml, and freeze-drying the solution in the same manner as in Example 1. (Approximately 50% etoposide-2-dimethylamino and 50% lactose) [0029]

【Effect of the invention】

Next, the fact that the freeze-dried preparation of etoposide-2-dimethylamino compound of the present invention has excellent storage stability and improved re-dissolution properties will be explained using actual experimental examples. [0030] Experimental Examples The products of the present invention shown in Examples 1 to 15 and volatile acids
The samples obtained in Control Example 1, which was freeze-dried after adjusting H, and Control Example 2, which was freeze-dried by adding only sugars without adjusting pH, were subjected to harsh conditions immediately after freeze-drying and at 60 to 65°C for one week. Storage, appearance, resolubility, pH and etoposide-2
-The residual rate of the dimethylamino compound was measured. The residual rate was determined by liquid chromatography, and the total amount of etoposide-2-dimethylamino compound and decomposition products was determined as 100. Examples 1 to 8 were added to the vial so that the resolubility was 10 mg/ml as etoposide-2-dimethylamino compound hydrochloride.
and Control Examples 1-2, 1 ml of distilled water, Examples 9-15
This was carried out by adding 2 ml of distilled water, and the ease of dissolving the dry powder and the presence or absence of precipitation of crystals after dissolution were observed. [0031] As a result, both Control Examples 1 and 2 had a pH of 5 or more, and crystals precipitated during redissolution, making them unsuitable for use as injection preparations. On the other hand, as shown in Table 1, the formulations of Examples 1 to 15 of the present invention had good resolubility, no crystal precipitation was observed, and p.
The change in H was also relatively small, and as a result of measuring the residual rate, the storage stability was also good. Furthermore, the residual rate was further improved by adding sugars. [0032] Table 1 Sample appearance Re-solubility pH Remaining rate (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Implementation Example 12 Example 13 Example 14 Example 15 Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good 89.8 93.4 99.1 99.3 99.1 98.4 88.5 93.2 90.4 98.9 99.0 99.1 99.4 98.2 98.4 [0033] As described above, the present invention improves resolubility. It was possible to obtain a preparation of etoposide-2-dimethylamino compound which was favorable and stable in both pH and residual rate.

Claims (3)

[Claims] Claim 1: 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-2-dimethylamino-2- Freeze-dried preparation of (deoxy-β-D-glucopyranoside) hydrochloride. 2. The lyophilized preparation according to claim 1, wherein at least one type of saccharide is added as a stabilizer. Claim 3: (1) Phosphoric acid and its alkali metal salt about 2
0 to about 30 w/w% and (2) 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-2-
A lyophilized preparation comprising (3) about 30 to about 50% w/w of (dimethylamino-2-deoxy-β-D-glucopyranoside) hydrochloride and (3) about 30 to about 50% of lactose.